Surfaceome Profiling of Cell Lines and Patient-Derived Xenografts Confirm FGFR4, NCAM1, CD276, and Highlight AGRL2, JAM3, and L1CAM as Surface Targets for Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The prognosis for patients with high-grade and metastatic disease is still very poor, and survivors are burdened with long-lasting side effects. Therefore, more effective and less toxic therapies are needed. Surface proteins are ideal targets for antibody-based therapies, like bispecific antibodies, antibody-drug conjugates, or chimeric antigen receptor (CAR) T-cells. Specific surface targets for RMS are scarce. Here, we performed a surfaceome profiling based on differential centrifugation enrichment of surface/membrane proteins and detection by LC-MS on six fusion-positive (FP) RMS cell lines, five fusion-negative (FN) RMS cell lines, and three RMS patient-derived xenografts (PDXs). A total of 699 proteins were detected in the three RMS groups. Ranking based on expression levels and comparison to expression in normal MRC-5 fibroblasts and myoblasts, followed by statistical analysis, highlighted known RMS targets such as FGFR4, NCAM1, and CD276/B7-H3, and revealed AGRL2, JAM3, MEGF10, GPC4, CADM2, as potential targets for immunotherapies of RMS. L1CAM expression was investigated in RMS tissues, and strong L1CAM expression was observed in more than 80% of alveolar RMS tumors, making it a practicable target for antibody-based therapies of alveolar RMS

First results on the running coupling in QCD with two massless flavours

We report on the non-perturbative computation of the running coupling of two-flavour QCD in the Schr"odinger functional scheme. The corresponding Lambda-parameter, which describes the coupling strength at high energy, is related to a low energy scale which still remains to be connected to a hadronic ``experimentally'' observable quantity. We find the non-perturbative evolution of the coupling indispensable to avoid untolerable errors in the estimated Lambda-parameter.Comment: 14 pages, 5 figures, 3 tables, some changes in the data analysis after discovery and correction of an error in Nucl. Phys. B 525, 387 (1998) by C. Christou et al. (hep-lat/9801007v2, Erratum to appear

Association of perinatal sentinel events, placental pathology and cerebral MRI in neonates with hypoxic-ischemic encephalopathy receiving therapeutic hypothermia

OBJECTIVE: Placental pathology might provide information on the etiology of hypoxic-ischemic encephalopathy (HIE). To evaluate the association of perinatal sentinel events (PSE), placental pathology and cerebral MRI in cooled neonates with moderate/severe HIE. STUDY DESIGN: Retrospective analysis of 52 neonates with HIE registered in the Swiss National Asphyxia and Cooling Register 2011-2019. PSE and Non-PSE groups were tested for association with placental pathology. Placental pathology categories were correlated with MRI scores. RESULTS: In total, 14/52 neonates (27%) had a PSE, 38 neonates (73%) did not have a PSE. There was no evidence for an association of occurrence of PSE and placental pathologies (p = 0.364). Neonates with high MRI scores tended to have more often chronic pathologies in their placentas than acute pathologies or normal placentas (p = 0.067). CONCLUSION: Independent of the occurrence of PSE, chronic placental pathologies might be associated with more severe brain injury and needs further study

Surfaceome Profiling of Cell Lines and Patient-Derived Xenografts Confirm FGFR4, NCAM1, CD276, and Highlight AGRL2, JAM3, and L1CAM as Surface Targets for Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The prognosis for patients with high-grade and metastatic disease is still very poor, and survivors are burdened with long-lasting side effects. Therefore, more effective and less toxic therapies are needed. Surface proteins are ideal targets for antibody-based therapies, like bispecific antibodies, antibody-drug conjugates, or chimeric antigen receptor (CAR) T-cells. Specific surface targets for RMS are scarce. Here, we performed a surfaceome profiling based on differential centrifugation enrichment of surface/membrane proteins and detection by LC-MS on six fusion-positive (FP) RMS cell lines, five fusion-negative (FN) RMS cell lines, and three RMS patient-derived xenografts (PDXs). A total of 699 proteins were detected in the three RMS groups. Ranking based on expression levels and comparison to expression in normal MRC-5 fibroblasts and myoblasts, followed by statistical analysis, highlighted known RMS targets such as FGFR4, NCAM1, and CD276/B7-H3, and revealed AGRL2, JAM3, MEGF10, GPC4, CADM2, as potential targets for immunotherapies of RMS. L1CAM expression was investigated in RMS tissues, and strong L1CAM expression was observed in more than 80% of alveolar RMS tumors, making it a practicable target for antibody-based therapies of alveolar RMS

Risk Factors and Treatment Outcomes of 1,375 Patients with Testicular Leydig Cell Tumors: Analysis of Published Case Series Data

AIMS Leydig cell tumors (LCTs) are rare but the most common non-germ cell testicular tumors. Only limited evidence exists for reliably differentiating between benign and malignant LCTs and for optimally managing the different types and stages of this rare disease. This review aims to synthesize the available evidence regarding the clinical presentation and clinicopathological characteristics associated with LCT malignancy and management. METHODS We analyzed published case series with LCTs patients. The association between clinicopathological variables and the presence of metastatic disease was assessed using regression analyses. RESULTS We included 357 reports, reviewing available data from 1,375 patients (median age: 34y). Testis-sparing surgery (TSS) was performed in 463 patients. Local recurrence after TSS occurred in 8 of 121 (7%) patients with available follow-up information. Metastases were found in 101 patients and were most often located in the retroperitoneal lymph nodes (60%), lungs (38%), and/or liver (29%). The multivariable models with or without multiple imputation predicting metastatic disease included older age, larger tumor size, the presence of any adverse factor (larger tumor diameter, necrosis, angiolymphatic invasion, pleomorphism, high mitotic index, atypia), and any protective factor (Reinke crystals, lipofuscin pigments, gynecomastia) with model AUCs of 0.93. Durable remission after resection of metastases or platinum-based chemotherapy was rarely seen. CONCLUSION Our risk tables using clinicopathological parameters can help identify patients harboring malignant tumors. These patients should undergo staging and either be followed or receive further treatment. In metastatic disease surgical and systemic treatment might result in disease control in in some patients

Minimally invasive, imaging guided virtual autopsy compared to conventional autopsy in foetal, newborn and infant cases: study protocol for the paediatric virtual autopsy trial

BACKGROUND: In light of declining autopsy rates around the world, post-mortem MR imaging is a promising alternative to conventional autopsy in the investigation of infant death. A major drawback of this non-invasive autopsy approach is the fact that histopathological and microbiological examination of the tissue is not possible. The objective of this prospective study is to compare the performance of minimally invasive, virtual autopsy, including CT-guided biopsy, with conventional autopsy procedures in a paediatric population. METHODS/DESIGN: Foetuses, newborns and infants that are referred for autopsy at three different institutions associated with the University of Zurich will be eligible for recruitment. All bodies will be examined with a commercial CT and a 3 Tesla MRI scanner, masked to the results of conventional autopsy. After cross-sectional imaging, CT-guided tissue sampling will be performed by a multifunctional robotic system (Virtobot) allowing for automated post-mortem biopsies. Virtual autopsy results will be classified with regards to the likely final diagnosis and major pathological findings and compared to the results of conventional autopsy, which remains the diagnostic gold standard. DISCUSSION: There is an urgent need for the development of alternative post-mortem examination methods, not only as a counselling tool for families and as a quality control measure for clinical diagnosis and treatment but also as an instrument to advance medical knowledge and clinical practice. This interdisciplinary study will determine whether virtual autopsy will narrow the gap in information between non-invasive and traditional autopsy procedures. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01888380

Post-mortem magnetic resonance imaging with computed tomography-guided biopsy for foetuses and infants: a prospective, multicentre, cross-sectional study

BACKGROUND: Post-mortem imaging has been suggested as an alternative to conventional autopsy in the prenatal and postnatal periods. Noninvasive autopsies do not provide tissue for histological examination, which may limit their clinical value, especially when infection-related morbidity and mortality are suspected. METHODS: We performed a prospective, multicentre, cross-sectional study to compare the diagnostic performance of post-mortem magnetic resonance imaging with computed tomography-guided biopsy (Virtopsy®) with that of conventional autopsy in foetuses and infants. Cases referred for conventional autopsy were eligible for enrolment. After post-mortem imaging using a computed tomography scanner and a magnetic resonance imaging unit, computed tomography-guided tissue sampling was performed. Virtopsy results were compared with conventional autopsy in determining the likely final cause of death and major pathologies. The primary outcome was the proportion of cases for which the same cause of death was determined by both methods. Secondary outcomes included the proportion of false positive and false negative major pathological lesions detected by virtopsy and the proportion of computed tomography-guided biopsies that were adequate for histological examination. RESULTS: Overall, 101 cases (84 fetuses, 17 infants) were included. Virtopsy and autopsy identified the same cause of death in 91 cases (90.1%, 95% CI 82.7 to 94.5). The sensitivity and specificity of virtopsy for determining the cause of death were 96.6% (95% CI 90.6 to 98.8) and 41.7% (95% CI 19.3 to 68.0), respectively. In 32 cases (31.7%, 95% CI 23.4 to 41.3), major pathological findings remained undetected by virtopsy, and in 45 cases (44.6%, 95% CI 35.2 to 54.3), abnormalities were diagnosed by virtopsy but not confirmed by autopsy. Computed tomography-guided tissue sampling was adequate for pathological comments in 506 of 956 biopsies (52.7%) and added important diagnostic value in five of 30 cases (16.1%) with an unclear cause of death before autopsy compared with postmortem imaging alone. In 19 of 20 infective deaths (95%), biopsies revealed infection-related tissue changes. Infection was confirmed by placental examination in all fetal cases. CONCLUSIONS: Virtopsy demonstrated a high concordance with conventional autopsy for the detection of cause of death but was less accurate for the evaluation of major pathologies. Computed tomography-guided biopsy had limited additional diagnostic value. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01888380)

Clinicopathologic and molecular analysis of embryonal rhabdomyosarcoma of the genitourinary tract: evidence for a distinct DICER1-associated subgroup.

Embryonal rhabdomyosarcoma (ERMS) of the uterus has recently been shown to frequently harbor DICER1 mutations. Interestingly, only rare cases of extrauterine DICER1-associated ERMS, mostly located in the genitourinary tract, have been reported to date. Our goal was to study clinicopathologic and molecular profiles of DICER1-mutant (DICER1-mut) and DICER1-wild type (DICER1-wt) ERMS in a cohort of genitourinary tumors. We collected a cohort of 17 ERMS including nine uterine (four uterine corpus and five cervix), one vaginal, and seven urinary tract tumors. DNA sequencing revealed mutations of DICER1 in 9/9 uterine ERMS. All other ERMS of our cohort were DICER1-wt. The median age at diagnosis of patients with DICER1-mut and DICER1-wt ERMS was 36 years and 5 years, respectively. Limited follow-up data (available for 15/17 patients) suggested that DICER1-mut ERMS might show a less aggressive clinical course than DICER1-wt ERMS. Histological features only observed in DICER1-mut ERMS were cartilaginous nodules (6/9 DICER1-mut ERMS), in one case accompanied by foci of ossification. Recurrent mutations identified in both DICER1-mut and DICER1-wt ERMS affected KRAS, NRAS, and TP53. Copy number analysis revealed similar structural variations with frequent gains on chromosomes 2, 3, and 8, independent of DICER1 mutation status. Unsupervised hierarchical clustering of array-based whole-genome DNA methylation data of our study cohort together with an extended methylation data set including different RMS subtypes from genitourinary and extra-genitourinary locations (n = 102), revealed a distinct cluster for DICER1-mut ERMS. Such tumors clearly segregated from the clusters of DICER1-wt ERMS, alveolar RMS, and MYOD1-mutant spindle cell and sclerosing RMS. Only one tumor, previously diagnosed as ERMS arising in the maxilla of a 6-year-old boy clustered with DICER1-mut ERMS of the uterus. Subsequent sequencing analysis identified two DICER1 mutations in the latter case. Our results suggest that DICER1-mut ERMS might qualify as a distinct subtype in future classifications of RMS

Risk factors and outcome in patients with primary sclerosing cholangitis with persistent biliary candidiasis

Background: Candidiasis is commonly observed in patients with primary sclerosing cholangitis (PSC), but the clinical risk factors associated with its presence have not been fully investigated. In this study, we aimed to analyse the incidence, risk factors, and transplantation-free survival in primary sclerosing cholangitis (PSC) patients with persistent biliary candidiasis. Methods: We retrospectively analysed patients diagnosed with PSC who were admitted to our department during 2002 to 2012. One-hundred fifty patients whose bile cultures were tested for fungal species were selected, and their clinical and laboratory parameters were investigated. The results of endoscopic retrograde cholangiography (ERC) and bile cultures were analysed using chart reviews. The cases of biliary candidiasis were sub-classified as transient or persistent. Results: Thirty out of 150 (20.0%) patients had biliary candidiasis. Although all patients demonstrated comparable baseline characteristics, those with biliary candidiasis showed significantly reduced transplantation-free survival (p < 0.0001) along with a markedly elevated frequency of cholangiocarcinoma (CCA) (p = 0.04). The patients were further sub-classified according to the transient (15/30) or persistent (15/30) nature of their biliary candidiasis. A subgroup analysis showed reduced survival with a greater necessity for orthotopic liver transplantation (OLT) only in patients with persistence of Candida (p = 0.007). The survival in the patients with transient biliary candidiasis was comparable to that in candidiasis-free patients. In a multivariate regression analysis that included Mayo risk score (MRS), sex, age, dominant stenosis, inflammatory bowel disease, autoimmune hepatitis overlap syndrome, and number of times ERC was performed, biliary candidiasis was an independent risk factor for reduced survival (p = 0.008). Risk factors associated with acquisition of biliary candidiasis were age at PSC diagnosis and number of ERCs. Conclusions: The persistence of biliary candidiasis is associated with markedly reduced transplantation-free survival in PSC patients. By contrast, actuarial survival in patients with transient biliary candidiasis approaches that for patients without any evidence of biliary candidiasis. Further studies on the treatment of persistent biliary candidiasis in patients with PSC are warranted

Fortschritte beim Aufbau Ost: Forschungsbericht wirtschaftswissenschaftlicher Forschungsinstitute über die wirtschaftliche Entwicklung in Ostdeutschland

Trotz der unbestreitbaren Fortschritte beim Aufbau Ost ist die wirtschaftliche Lage in Ostdeutschland unbefriedigend. Nicht nur, dass das gesamtwirtschaftliche Wachstum seit einigen Jahren hinter dem in Westdeutschland zurückbleibt und die Unterbeschäftigung auf hohem Niveau verharrt, gravierender noch ist, dass die Gefahr besteht, dass Mutlosigkeit und Resignation an Gewicht gewinnen. Die Erfolge, die seit Anfang der neunziger Jahre zu verzeichnen sind, treten dabei in den Hintergrund - Erfolge bei der Erneuerung der Infrastruktur, dem Aufbau einer wettbewerbsfähigen Unternehmensbasis sowie - und nicht zuletzt - bei der Verbesserung der materiellen Lebensverhältnisse der Menschen. Das Bundesministerium der Finanzen hat vor diesem Hintergrund fünf wirtschaftswissenschaftliche Forschungsinstitute beauftragt, in jährlichen „Fortschrittsberichten" ausgewählte Aspekte der wirtschaftlichen Entwicklung in den neuen Bundesländern zu begutachten. Diese fünf Institute - das Deutsche Institut für Wirtschaftsforschung Berlin (DIW), das Institut für Arbeitsmarkt- und Berufsforschung (IAB), das Institut für Weltwirtschaft an der Universität Kiel (IfW), das Institut für Wirtschaftsforschung Halle (IWH) und das Zentrum für Europäische Wirtschaftsforschung (ZEW) - haben soeben ihren ersten gemeinsamen Bericht fertiggestellt. 1 Ausgewählte Ergebnisse werden im Folgenden präsentiert. Den Bericht durchzieht - gleichsam als roter Faden - die Erkenntnis, dass die Lage in Ostdeutschland keineswegs so hoffnungslos ist, wie es in der Öffentlichkeit vielfach dargestellt wird. Hoffnung macht vor allem, dass die Industrie einen robusten Wachstumspfad eingeschlagen hat. Hoffnung macht auch, dass zunehmend mehr Unternehmen des Verarbeitenden Gewerbes im weltweiten Wettbewerb mithalten können und auf den internationalen Märkten expandieren. Das bedeutet zugleich, dass die Entwicklung der ostdeutschen Wirtschaft immer mehr vom allgemeinen Wirtschaftsverlauf bestimmt wird. In dem Maße, in dem die Anpassungskrise in der Bauwirtschaft überwunden werden kann, ist bei einer Verbesserung des konjunkturellen Umfelds auch wieder mit höheren gesamtwirtschaftlichen Wachstumsraten zu rechnen. Gleichwohl ist nicht zu verkennen, dass die wirtschaftlichen Probleme der neuen Bundesländer alles andere als gering sind. Denn es zeigen sich strukturelle Defizite, die, wie alle regionalökonomischen Erfahrungen lehren, nur langfristig gelöst werden können. Dabei sollte der Blick mehr als bisher auf die einzelnen Regionen der neuen Bundesländer gerichtet werden, denn Ostdeutschland ist auch in wirtschaftlicher Hinsicht kein einheitliches Ganzes. Weil es Zeit braucht, die noch bestehenden Strukturprobleme zu lösen, verbietet es sich, den Menschen übertriebene Hoffnungen zu machen. Das würde nur weitere Enttäuschungen nach sich ziehen. Ohne Zweifel bedarf es weiterer wirtschaftpolitischer Anstrengungen für den „Aufbau Ost". Nach Ansicht der Institute kommt es weiterhin vor allem darauf an, durch Investitionen die Standortbedingungen in Ostdeutschland zu verbessern; die Kompensation von Standortdefiziten durch Subventionen sollte hingegen zurückgeführt werden. Mehr Bedeutung als bisher sollte überdies Investitionen in das Humankapital eingeräumt werden - das gebietet die gegenwärtige und erst recht die absehbare demographische Entwicklung. --